[A Case of Autoimmune Acquired Factor XIII Deficiency Diagnosed from Recurrent Postoperative Bleeding].

The patient was a 79-year-old man with ureteroileal anastomotic stricture after a Bricker ileal conduit. Endourological treatment of stenosis was performed via percutaneous nephrostomy and ileal conduit. The patient experienced lower abdominal pain on the following day, and computed tomographic (CT) scan showed hematoma retention around the kidney and active bleeding from the renal artery branches. Transarterial embolisation (TAE) was performed and the bleeding was controlled. Two days later, there was a sudden progression of anemia and CT showed an increase in hematoma around the kidney. We subsequently performed nephrectomy for hemostasis. Five days later, the anemia progressed further. There was hematoma retention in the retroperitoneal cavity, and emergency laparotomy hemostasis was performed. Routine coagulation test results were normal. Heavy bleeding was observed several days after TAE and the possibility of coagulation factor XIII deficiency was considered. Factor XIII deficiency was confirmed by a low factor XIII activity level. The patient was given plasma-derived factor XIII. After receiving factor XIII replacement, factor XIII activity remained unchanged and the patient continued to bleed. Thereafter, a cross-mixing test was performed and the patient was diagnosed with autoimmune acquired factor XIII deficiency. Cortical steroids were administered to remove the factor XIII inhibitor. Steroid administration showed a rapid increase in factor XIII activity, and bleeding symptoms were no longer observed. In cases of serious bleeding of unknown cause with a normal coagulation profile, acquired factor XIII deficiency should be suspected and factor XIII activity measured.

Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy.

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.

Coexistence of HLA and KIR ligand mismatches as a risk factor for viral infection early after cord blood transplantation.

Viral infection is one of the lethal adverse events after cord blood transplantation (CBT). Human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) ligand divergences can increase the risk of viral infection due to conflicting interactions between virus-infected cells and immune cells. However, the relationship between these disparities and the frequency of viral infection after CBT remains to be evaluated. Herein, we have conducted a retrospective multicenter study to assess the effect of HLA and KIR ligand mismatches on viral infections after CBT. The study included 429 patients, among which 126 viral infections occurred before day 100. Viral infection was significantly associated with poorer overall survival (OS; hazard ratio [HR] 1.74, p < 0.01). Patients harboring ≥3 mismatches in the HLA allele and inhibitory KIR ligand mismatches (HLA & KIR mismatches) had a significantly greater prevalence of viral infection (HR 1.66, p = 0.04). Thus, patients with HLA & KIR mismatches had poorer outcomes in terms of non-relapse mortality (HR 1.61, p = 0.05). Our study demonstrates the unfavorable impacts of HLA & KIR mismatches on viral infections and non-relapse mortality after CBT. Evaluating the viral infection risk and performance of an appropriate and early intervention in high-risk patients and optimizing the graft selection algorithm could improve the outcome of CBTs.

Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes.

STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.This article is highlighted in the In This Issue feature, p. 747.

Molecular pathogenesis of disease progression in MLL-rearranged AML.

Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

Splenic mass in a case of CALR-mutated essential thrombocythemia.

We report here an intrasplenic large mass in an elderly case of essential thrombocythemia (ET)-myelofibrosis. Laparoscopic splenectomy revealed extramedullary hematopoiesis (EMH) and a type 1 CALR gene mutation (CALR-c.1092_1143del52) in the splenic mass. It remains to be determined if CALR-mutated ET has an increased tendency to develop mass-forming EMH.

Integrated molecular analysis of adult T cell leukemia/lymphoma.

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

[Successful treatment with recombinant thrombomodulin for disseminated intravascular coagulation complicated with hemophagocytic syndrome].

Recombinant human thrombomodulin (rTM) improves the blood coagulation disorder characteristic of disseminated intravascular coagulation (DIC) as well as, or even better than, other anti-DIC drugs. On post-marketing surveillance, its effectiveness has been recognized for hematologic disorders, sepsis and solid tumor subgroups. However, the effect on hemophagocytic syndrome (HPS) complicated by DIC remains unclear. We treated three HPS patients with rTM in addition to chemotherapy for the underlying diseases including nasal NK/T cell lymphoma, angioimmunoblastic T-cell lymphoma and refractory acute myeloid leukemia post cord blood transplantation. Although being refractory to medical management was suspected in our cases, clinical status rapidly came under control including not only amelioration of the blood coagulation disorder but also inflammatory reactions, such as serum ferritin and lactic acid dehydrogenase abnormalities, which represent HPS activity. These observations suggest that rTM might exert marked synergistic effects on HPS with DIC. Given the results obtained in these three cases, administration of rTM appears to offer a promising method of treating HPS complicated by DIC.

Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly complicated by the onset of acute myeloid leukemia.

We herein describe the case of a 62-year-old woman who presented with anemia and an 8-month history of weight loss. Bone marrow aspiration showed increased myeloblasts. The histopathology findings of biopsy specimens of the right cervical lymph node and intestinal mass indicated B-lymphoproliferative disorder (B-LPD) with Hodgkin lymphoma-like morphologic features and polymorphous diffuse large B-cell lymphoma (DLBCL), respectively. In addition, both types of lymphoma cells were positive for Epstein-Barr virus (EBV)-encoded small RNA-1. The patient was diagnosed with EBV-associated B-LPD and simultaneous acute myeloid leukemia (AML). This is the first case of a patient diagnosed with simultaneous EBV-positive DLBCL of the elderly and AML.

Successful treatment of a patient with multicentric Castleman's disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody.

We herein describe an unusual case of multicentric Castleman's disease accompanied by thrombocytopenia, ascites, renal failure and myelofibrosis in a Japanese woman. The patient was initially diagnosed as having myelodysplastic syndrome with myelofibrosis. The general condition of the patient deteriorated rapidly; however, treatment with tocilizumab, an anti-interleukin-6 receptor antibody, together with corticosteroids dramatically improved her symptoms. The clinical features of this case were similar to those of three cases previously reported by Takai et al. (Rinsho Ketsueki, 2010, 51:320-5), which were determined to be thrombocytopenia, anasarca, fever, reticulin myelofibrosis and organomegaly (TAFRO) syndrome, a possibly distinct clinical entity.

Development of donor cell leukemia mimicking hematogones after unrelated cord blood transplantation for relapsed acute lymphoblastic leukemia.

A 26-year-old woman, who developed ALL when she was eighteen years old, achieved remission after chemotherapy. Her ALL relapsed when she was twenty-two years old. After re-induction therapy, she underwent cord blood transplantation. Her bone marrow examination on the 42nd day revealed a lymphoblast count of 16%. She was observed without any therapy, but her bone marrow blast count continued to be around 6% for three years without any symptoms. The bone marrow blast fraction originated from the cord blood. Surface marker analysis of the blast fraction initially revealed a pattern of hematogones that was CD10 and CD19 positive, but then showed a myeloblast pattern that was CD13 and CD33 positive. AML developed as donor cell leukemia. When blasts appear in the early phase after transplantation and persist, an observation period is necessary with molecular chimerism, morphology, and surface marker analysis of the blast fraction to consider relapse, hematogones, or donor cell leukemia.

Acute renal failure associated with systemic polyoma BK virus activation in a patient with peripheral T-cell lymphoma.

Renal dysfunction associated with polyoma BK virus (BKV) reactivation usually occurs in the setting of profound immunosuppression related to renal transplantation and hematopoietic stem cell transplantation. However, it has been rarely described as a complication during the course of conventional chemotherapy. Here, we report a case of BKV-associated acute renal failure developed in a patient suffering from refractory peripheral T-cell lymphoma, not otherwise specified. After repetitive cycles of salvage chemotherapy, the patient developed fever and urinary frequency, rapidly followed by anuria that necessitated the emergent institution of hemodialysis. Cytologic examination of the urine revealed the presence of decoy cells and positive immunostaining for polyomavirus simian virus 40 antigen. High levels of BKV were detected in urine and plasma with quantitative real-time polymerase chain reaction, strongly suggesting that his renal failure was due to polyoma virus-associated nephropathy. This rare complication should be kept in mind in case of unexplained renal failure developed in immunodeficient patients undergoing cytotoxic chemotherapy.